Project Summary The use of 18F-containing radiotracers is an important tool for PET imaging. While numerous methods have been developed to synthesize molecules containing trifluoromethyl groups, the translation of these methods to form CF218F groups is not well established. The known [18F]trifluoromethylation methods require harsh reagents, electrophilic 18F sources, high temperatures or stoichiometric amounts of metal. These conditions contribute to limited substrate scope or utility of the method. The use of electrophilic fluorine produces products in low specific activity or low yields, making separation difficult or time consuming. Decarboxylative methods have recently been shown to be a promising strategy to access monofluorinated molecules. However, current decarboxylative [18F]trifluoromethylation methods involve high temperatures, and are only applicable to aryl and heterocyclic containing substrates The ideal decarboxylative approach to install CF2?18F/19F groups would require mild conditions and provide access to a broader scope, permitting further transformation to biologically- relevant molecules. In this proposal, we present a novel and practical method for the synthesis of trifluoromethyl groups that can easily be adapted for [18F]trifluoromethylation chemistry. We propose a decarboxylative nucleophilic CF2?F bond formation strategy. This method employs redox-active esters and a photoredox catalyst to assist in the decarboxylation. The redox-active ester can be generated in situ and is also modular, to allow for tuning and favorable decarboxylation. The photocatalyst is important for both the reduction of the ester, and oxidation of the RCF2 radical to the cation. The use of the photoredox catalyst, limits the need for additional stoichiometric redox reagents. The nucleophilic fluorine source is important for trapping the RCF2 cation. Commercially available HF sources proposed are mild and allow for easy reaction set ups. This method allows access to trifluoromethylation of aryl and aliphatic substrates containing sensitive functional groups, such as amines or alcohols. Successful development of this methodology will provide its application to [18F]trifluoromethylation, and further access to new 18F-radiotracers for PET imaging.